Compositions of omega 3 fatty acids to treat diseases which involve damage to the nervous system

ABSTRACT

Compositions comprising omega 3 fatty acids for use in the treatment, amelioration or prevention of various conditions, disorders, and diseases which involve damage to the nervous system, as the peripheral nervous system neuropathy and glaucoma.

TECHNICAL FIELD OF THE INVENTION

The present invention relates generally to the fields of medicine,foods, and health food supplements. More particularly, it relates tocompositions comprising omega 3 fatty acids for use in the treatment ofa disease, and in particular to compositions comprising eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA) for use in the treatment,amelioration or prevention of various conditions, disorders, anddiseases which involve damage to the nervous system, as the peripheralnervous system neuropathy and glaucoma.

BACKGROUND OF THE INVENTION

Neuropathy is damage or disease involving nerves, which may affectsensation, movement, gland or organ function and other aspects ofhealth, depending on the type of nerve affected. Common causes includesystemic diseases (such as diabetes or leprosy), vitamin deficiency,medication (e.g., chemotherapy), traumatic injury, excessive alcoholconsumption, immune system disease or infection, or it may be inherited(present from birth).

Peripheral neuropathy (PN) is damage or disease involving nerves, whichmay affect sensation, movement, gland or organ function and otheraspects of health, depending on the type of nerve affected. Commoncauses include systemic diseases (such as diabetes or leprosy), vitamindeficiency, medication (e.g., chemotherapy), traumatic injury, excessivealcohol consumption, immune system disease or infection, or it may beinherited (present from birth).

The prevalence of peripheral neuropathy in the family medicine settingis 8 percent in persons 55 years and older. (Martyn & Hughes 1997. JNeurol Neurosurg Psychiatry. 62(4):310-318). The prevalence in thegeneral population may be as high as 2.4 percent (Hughes 2002. BMJ.324(7335):466-469). A community-based study estimated the prevalence ofperipheral neuropathy in patients with type 2 diabetes mellitus to be26.4 percent (Davies et al., 2006. Diabetes Care. 29(7):1518-1522).

The peripheral nervous system (PNS, or occasionally PeNS) is the part ofthe nervous system consisting of the nerves and ganglia outside of thebrain and spinal cord. The cranial nerves are part of the PNS with theexception of cranial nerve II, the optic nerve, along with the retina.The second cranial nerve is not a true peripheral nerve but a tract ofthe diencephalon. Cranial nerve ganglia originate in the CNS. However,the remaining eleven cranial nerve axons extend beyond the brain and aretherefore considered part of the PNS.

3^(rd), 4^(th), 6^(th), 7^(th) Cranial Neuropathies

Facial neuropathy produces weakness of the muscles of facial expressionand eye closure. Voluntary eye closure may not be possible and canresult in damage to the cornea and conjunctiva.

Eye movements are subserved by the ocular motor nerves (cranial nerves3,4 and 6) which innervate the 6 muscles of each eye. The oculomotor(3rd) nerve innervates the medial rectus, inferior rectus, superiorrectus and inferior oblique as well as the levator palpebrae. Thetrochlear (4th) nerve innervates the superior oblique muscle and theabducens (6^(th)) nerve innervates the lateral rectus muscle. Facial andocular motor nerves neuropathies can be due to ischaemia, inflammationand/or trauma. There is no current treatment for these eye pathologies.

Other Eye Pathologies Due to Inflammation

Conditions like scleritis, thyroid eye disease, chronic uveitis andkeratoconjunctivitis are due to inflammation. Current treatments includesteroids and immunosuppressive agents.

Conjunctival and corneal wounds can be due to inflammation or due todecreased sensation of the nerve supplies.

There is a need for more effective and/or alternative therapies fortreating the above conditions.

Optic Nerve Damage

Optic nerve damage can occur mainly due to glaucoma, ischaemia,inflammation or trauma. Currently there is no treatment to limit axonalinjury and improve neuronal function in these patients.

Optic Nerve Damage Due to Glaucoma

Glaucoma is the second leading cause of blindness worldwide, effecting80 million with approximately 7 million people blind. It affects 1-2% ofthe US population.

Glaucoma consists of a group of disorders that lead to retinal ganglioncell death. In most forms of glaucoma elevated intraocular pressure isconsidered the single most important factor for developing glaucoma.However, high intraocular pressure is not present in some forms ofglaucoma like Normal Tension Glaucoma.

It is characterized by progressive damage to the optic nerve,accompanied by gradual loss of the visual field, starting at theperiphery and extending to the centre. It may or may not directlyrelated to the level of intraocular pressure.

It can be divided into 3 main groups:

-   -   1) Open angle glaucoma, which is subdivided into high pressure        glaucoma (primary open angle glaucoma), and normal pressure        glaucoma (normal tension glaucoma)    -   2) Closed angle glaucoma    -   3) Secondary glaucoma

In glaucoma there is a breakdown of blood-retina barrier. This resultsin inflammatory response and damage to retinal ganglion cells byvascular dysregulation resulting in periods of ischaemia and reperfusiondamage. As a result of ischaemia there is elevation of inflammatorycytokines and chemokines such as VEGF, TNF-a, IL, CRP, NO etc. Alsoincrease of endothelin-1 which is a vasoconstrictive, thus promotinghypoxia and ischaemia which result in retinal ganglion cell death.

It is a chronic disease and the current mainstay of therapy is aimed atlowering intraocular pressure to slow disease progression.

Medication in terms of eye drops is the usually accepted first linetreatment followed by laser treatment and incisional surgery. The goalof therapy is to reduce the intraocular pressure by at least 20% giventhe results of OHTS, AGIS and the EMGT studies which showed reduction ofat least 40% of rates of worsening of field testing versus no treatment.There is a higher risk of field loss among patients who have largerintraocular pressure swings at different times of the day.

Late diagnosis or advanced visual field loss at the time of diagnosisare among the primary risk factors for progression to blindness inglaucoma. It has been estimated that late presentation is the main causeof blindness in one-third of glaucoma patients who become blind.

With growing aging population there is an increase of glaucoma blindnessin the world. Understanding glaucoma pathophysiology we can betterimprove our treatments to improve care for our glaucoma patients.

60% of glaucoma patients suffer from dry eye disease which can reducequality of life and compliance of glaucoma treatment. Multiple dailyexposures to the ocular surface to active compounds and preservativescan worsen the burden of dry eye disease in this population.

Glaucoma research has seen an increasing focus on neuroprotection. Evena small benefit in patients with advanced glaucoma damage with reducedvision would be beneficial.

Degeneration of retinal ganglion cells has been observed in diseases ofthe nervous system such as Parkinson's disease and Alzheimer's withoutglaucoma. Inflammation plays a role in these nervous system diseaseswhich also causes the damage to the retinal ganglion cells.

During the last 20 years, controlled clinical trials showed thatlowering intraocular pressure can slow glaucoma progression. Any newtreatment should have a neuroprotective effect to reduce the remainingprogression rate below that achieved by intraocular pressure-basedtherapy alone. The neuroprotective treatment must have minimal visual orsystemic side effects otherwise it will not be tolerated by patients.

Intraocular pressure lowering therapy slows the untreated rate ofprogression by about 50%. Therefore the aim of neuroprotection is toreduce the progression by another 50%.

Ischaemic Optic Neuropathy (ION)

95% of ION's are secondary to non-inflammatory small vessel disease. Therest are due to secondary vasculitis. Non arteritic anterior ischaemicoptic neuropathy (NAION) is the most common cause of acute opticneuropathy in patients over the age of 50 years old. It affects up to 10people per 100000. Symptoms include acute unilateral painless of vision.Any region in the visual field can be affected. More than 50% ofpatients with ION are blind (<20/200 vision) with constricted visualfields.

The mechanism of ischaemia remains unknown. Studies have shown thathypertension (47%-49%) and diabetes (24%-26%) were present in NAION.Sleep apnea, hypoperfusion, severe anaemia and nocturnal hypotension areall potential but unproven risk factors for NAION.

In most cases of ischaemic optic neuropathy vision worsens progressivelyover two weeks and then remains stable over time. The risk for thefellow eye is 15% within 5 years. Visual acuity appears to plateau roundthe time that disk oedema is superseded by optic atrophy.

Currently there is no generally accepted treatment for ischaemic opticneuropathy. Systemic steroids have been used to try to decreasecapillaries permeability and resolve the oedema faster. This wouldreduce compression of capillaries and improve the blood flow. In onestudy patients given oral steroids had resolution of oedema in 6.8 weekscompared to 8.2 weeks in untreated cases. Visual fields and vision canimprove up to maximum of 6 months but not thereafter. Intravitrealtramcinolone and intravitreal VEGF have been used and reported as casereports.

Optic Neuritis

Optic neuritis is an acute inflammatory demyelinating disorder of theoptic nerve that occurs most often in young adults and can be associatedwith multiple sclerosis. Even though good functional vision recovery isseen in most patients, some patients fail to recover (5-10%). Opticneuritis is the initial presentation of multiple sclerosis in up to 20%of patients. Ophthalmologists are usually the first doctors to seepatients with multiple sclerosis related visual symptoms. It is anautoimmune disease with perivascular infiltration of immune cells acrossthe blood brain barrier. These immune cells destroy the myelin and causedemyelination. Inflammatory cellular and humoral immune mechanisms playa major role in optic neuritis.

The optic neuritis treatment trial showed that 3 days of intravenousmethylprednisolone hastens visual recovery, although many patientsrecover vision regardless. Low dose oral steroids have shown to increasethe chance for recurrent optic neuritis and the reason is unclear.

Other Eye Pathologies Due to Inflammation

Conditions like scleritis, thyroid eye disease, chronic uveitis andkeratoconjunctivitis are due to inflammation. Current treatments includesteroids and immunosuppressive agents.

Conjunctival and corneal wounds can be due to inflammation or due todecreased sensation of the nerve supplies.

In summary, there is a need for more effective and/or alternativetherapies for treating the above conditions.

The compositions described in this patent represents a novel therapeuticapproach to reduce morbidity resulting from diseases which involvedamage to the nervous system, and particularly for use in treatment of2nd cranial (optic) nerve neuropathy, 3rd cranial nerve neuropathy(occulomotor), 4th cranial nerve neuropathy (trochlear), 6th cranialnerve neuropathy (abducent), 7th nerve neuropathy (facial), optic nervedamage, and other eye pathologies due to inflammation.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides novel compositions and dosage formscomprising omega 3 fatty acid for use in the treatment, amelioration orprevention of various conditions, disorders, and diseases which involvedamage to the nervous system, as the peripheral nervous systemneuropathy and glaucoma.

Thus, a first aspect of the present invention refers to a composition,hereinafter composition of the invention, comprising at least 3 g ofomega 3 fatty acids. In a preferred embodiment of the first aspect ofthe invention, the composition of the invention comprises at least 3.4 gof omega 3 fatty acids, and more preferably, at least 5 g of omega 3fatty acids.

In another preferred embodiment of the first aspect of the invention,the composition of the invention comprises from 5 g to 15 g of omega 3fatty acids.

In another preferred embodiment of the first aspect of the invention,the omega 3 fatty acid is selected from the list consisting of:eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alphaliniolenic acid (ALA), stearidonic acid (SA), oeicosatetraenoic acid, orany combination thereof. In a more preferred embodiment of the firstaspect of the invention, the omega 3 fatty acid is eicosapentaenoic acid(EPA).

In a further preferred embodiment of the first aspect of the invention,the omega 3 fatty acids are a combination of eicosapentaenoic acid (EPA)and docosahexaenoic acid (DHA). In a still further preferred embodimentof the first aspect of the invention, eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA) are in a mass ratio from 1:1 to 5:1. Stillmore preferably, the eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA) are in a mass ratio of about 2:1.

In a still further preferred embodiment of the first aspect of theinvention, said composition is a pharmaceutical composition whichoptionally comprises an acceptable pharmaceutical carrier and/oradditional active ingredients. More preferably, the pharmaceuticalcomposition comprises at least 50% weight omega 3 fatty acids.

In another preferred embodiment, the composition is an oral dosage form.More preferably the oral dosage form is selected from the groupcomprising tablets, capsules, caplets, slurries, sachets, suspensions,chewing gum, and powder formulation that may be dissolved in a liquid.In a still more preferably embodiment, the oral dosage form is asuspension. In another still more preferably embodiment, the oral dosageform is a powder.

In another preferred embodiment, the composition of the invention is afood composition or a health food supplement. More preferably, the foodcomposition comprises at least 50% weight omega 3 fatty acids.

A second aspect of the invention refers to a kit of parts comprisingeicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in a massratio from 1:1 to 5:1.

In a preferred embodiment of the second aspect of the invention, theeicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are a massratio of about 2:1.

In a still further preferred embodiment of the second aspect of theinvention, said kit of parts is a pharmaceutical kit of parts whichoptionally comprises an acceptable pharmaceutical carrier and/oradditional active ingredients. More preferably, the additional activeingredient is a steroid, an anti-drug or a nutritional supplement.

In another embodiment of the first aspect of the invention, said kit ofparts is a food composition.

A third aspect of the inventions refers to the composition or the kit ofparts of the invention, for use in therapy or for use as a medicament.

A fourth aspect of the invention refers to the composition or the kit ofparts of the invention, for its use in the treatment, amelioration orprevention of diseases which involve damage to the nervous system, asthe peripheral nervous system neuropathy and glaucoma.

In a preferred embodiment of the fourth aspect of the invention, thediseases which involve damage to the nervous system is selected from thegroup consisting of 2^(nd) cranial (optic) nerve neuropathy, 3^(rd)cranial nerve neuropathy (occulomotor), 4^(th) cranial nerve neuropathy(trochlear), 6^(th) cranial nerve neuropathy (abducent), 7^(th) nerveneuropathy (facial), optic nerve damage, and other eye pathologies dueto inflammation.

Optic nerve damage can occur mainly due to glaucoma, ischaemia,inflammation or trauma.

In a more preferred embodiment of the fourth aspect of the invention,the optic nerve damage is selected from the group consisting of opticnerve damage due to glaucoma, ischaemic optic neuropathy (ION), andoptic neuritis, or any combination thereof. In another preferredembodiment of the fifth aspect of the invention, the eye pathology dueto inflammation is selected from the group consisting of scleritis,thyroid eye disease, chronic uveitis, vernal and atopickeratoconjunctivitis, conjunctival and corneal wounds, A particularembodiment of the fourth aspect of the invention refers to thecomposition or the kit of parts of the invention, for its use in thetreatment, amelioration or prevention of glaucoma.

In a more preferred embodiment, the pharmaceutical composition or kit ofparts of the invention can be administered one or more times a day, forexample, 1, 2, 3 or 4 times a day, in a typical total daily amount to beabove 5 g per day of omega 3 fatty acids, more preferably to be above 5g per day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),and more preferably comprised between 5 g to 15 g per day. Preferably,the combined dosage is from 7.5g to 10g per day. In a more preferredembodiment, the pharmaceutical composition or kit of parts of theinvention can be administered in a dose wherein the combined EPA and DHAis such that the arachidonic acid/eicosapentaenoic acid mass ratio inthe blood is in the range of 0.8 to 3 preferably from 1 to 1.5.

A fifth aspect of the invention refers to the use of the foodcomposition of the invention, for the treatment, amelioration orprevention of diseases which involve damage to the nervous system, asthe peripheral nervous system neuropathy and glaucoma.

In a preferred embodiment of the fifth aspect of the invention, thediseases which involve damage to the nervous system is selected from thegroup consisting of 2^(nd) cranial (optic) nerve neuropathy, 3^(rd)cranial nerve neuropathy (occulomotor), 4_(th) cranial nerve neuropathy(trochlear), 6^(th) cranial nerve neuropathy (abducent), 7^(th) nerveneuropathy (facial), optic nerve damage, and other eye pathologies dueto inflammation.

Optic nerve damage can occur mainly due to glaucoma, ischaemia,inflammation or trauma.

In a more preferred embodiment of the fifth aspect of the invention, theoptic nerve damage is selected from the group consisting of optic nervedamage due to glaucoma, ischaemic optic neuropathy (ION), and opticneuritis, or any combination thereof. In another preferred embodiment ofthe fifth aspect of the invention, the eye pathology due to inflammationis selected from the group consisting of scleritis, thyroid eye disease,chronic uveitis, vernal and atopic keratoconjunctivitis, conjunctivaland corneal wounds, A particular embodiment of the fifth aspect of theinvention refers to the use of the food composition of the invention forthe treatment, amelioration or prevention of glaucoma. More preferably,the composition or the kit of parts of the invention is for use in thetreatment of a patient population that is poorly responsive ornonresponsive to steroids.

In a more preferred embodiment, the food composition of the inventioncan be administered one or more times a day, for example, 1, 2, 3 or 4times a day, in a typical total daily amount to be above 5 g per day ofomega 3 fatty acids, more preferably to be above 5 g per day ofeicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and morepreferably comprised between 5 g to 15 g per day. Preferably, thecombined dosage is from 7.5 g to 10 g per day. In a more preferredembodiment, the pharmaceutical composition or kit of parts of theinvention can be administered in a dose wherein the combined EPA and DHAis such that the arachidonic acid/eicosapentaenoic acid mass ratio inthe blood is in the range of 0.8 to 3 preferably between 1 to 1.5.

DESCRIPTION OF THE FIGURES

FIG. 1. Number of lines gained for advanced optic nerve damage due toglaucoma. Shows the number of lines gained and the number of eyes overthe study period. There is an increase of 1.5 lines of visual acuity at6 weeks and 2.1 lines at 3 months. In all cases the visual field testinghas improved. Average lines of gained at 3 months is 2 lines.

FIG. 2. Shows an example of a 65 year old male with controlledintraocular pressures with anti-glaucoma drops. Field testing shows theimprovement within 3 months of starting with 10 g per day of theinvention. The visual acuity also improved by 3.5 lines within the 3months. There is no previous art to show any improvement in visionacuity or any improvement in optic nerve function i.e. visual field.

FIG. 3. Shows another example of a 53 year old man with advancedglaucoma. His intraocular pressures are controlled withanti-glaucomatous eye drops. His visual acuity in the left eye was 20/50and has an advanced field loss as shown the field test. He was startedon 8 g of the composition of the invention per day. At 2.4 months hisgained 2 lines of vision and his field test improved as shown. There isno previous art to show any clinical improvement in vision or fieldtest.

FIG. 4. Number of lines gained for Ischaemic optic neuropathy. Shows thenumber of lines gained and the number of eyes over the period of 4.5months in the example 2. There is an increase of 1.6 lines of visualacuity at 6 weeks, 2.4 lines at 3 months and 2.5 lines at 4.5 months.There was also improved visual field testing in all the cases that weretested. Average lines gained at 3 months is 2.

FIG. 5. Shows an example of a 55 year old man who had ischaemic opticneuropathy 6 months previous to presentation in the clinic. His visualacuity was 20/50. He was started on 10 g/day of the compositionaccording to the invention. 5 months following treatment his visionimproved by 4 lines and the visual field test improved as shown.

FIG. 6. Shows an example of a 15 year old boy who presented 14 monthsfollowing a road traffic accident. His visual acuity was 20/40 and hadoptic nerve damage as shown with the field test. He was started on 7.5 gper day of the composition of the invention. 5.5 months followingtreatment his visual acuity improved by 2.5 lines and the field test hasimproved as shown.

DETAILED DESCRIPTION OF THE INVENTION

The present invention confronts the problem of to improve visual acuityand visual fields in patients with nerve damage, and in particular withoptic nerve damage due to glaucoma inflammation/ischaemia or trauma.

It has been found by the inventor that significant improvements in thevisual acuity (using the EDTRS electronic chart) and in signs andsymptoms of these conditions can be achieved using high doses of EPA,and preferably of EPA and DHA, in the indicated ratio and dosageamounts. The therapy is effective even for patients who arenon-responsive or poorly responsive to other therapies. The therapy ofthe invention is particularly suitable for oral administration. The useof EPA and DHA in the indicated ratios and dosage amounts also avoidsthe side effects experienced with the known treatments (eg. Steroids).

In some embodiments, the EPA and DHA are for use together with a furthertherapeutic agent for simultaneous, sequential or separateadministration. Preferably the further therapeutic agent is a steroidand/or immunosuppressive drug and/or other nutritional supplement.

The compositions and kit of parts of the invention can be used also incranial neuropathies, scleritis, thyroid eye disease, chronic uveitis,vernal/atopic keratoconjunctivitis, conjunctival and corneal wounds, andother body conditions due to inflammation and damaged nerves. High dosesomega 3 fatty acid supplementation may represent a significanttherapeutic option for such patients.

Compositions and Kit of Parts of the Invention

Thus, in accordance with a first aspect of the present invention, thereis provided a composition, hereinafter composition of the invention,comprising at least 3 g of omega 3 fatty acids, and more preferably 5 gof omega 3 fatty acids.

In a preferred embodiment of the first aspect of the invention, thecomposition of the invention comprises from 5 g to 15 g of omega 3 fattyacids.

An omega-3 fatty acid is an unsaturated fatty acid containing a finalcarbon-carbon double bond as the third bond from the alkyl end of themolecule (i.e. the end that is remote from the carboxylic acid group).Examples of omega-3 fatty acids are indicated in Table 1.

TABLE 1 Omega-3 fatty acids Lipid Common name name Chemical name MWTetracosahexaenoic 24:6 (n-3) all-cis-6,9,12,15,18,21- 357 acidtetracosahexaenoic acid Tetracosapentaenoic 24:5 (n-3)all-cis-9,12,15,18,21- 359 acid tetracosapentaenoic acid Docosahexaenoicacid 22:6 (n-3) all-cis-4,7,10,13,16,19- 328 (DHA) docosahexaenoic acidDocosapentaenoic acid 22:5 (n-3) all-cis-7,10,13,16,19- 331 (DPA)docosapentaenoic acid Eicosapentaenoic acid 20:5 (n-3)all-cis-5,8,11,14,17- 302 (EPA) eicosapentaenoic acid

Eicosatetraenoic acid (ETA) 20:4 (n-3)all-cis-8,11,14,17-eicosatetraenoic acid 304

Eicosatrienoic acid (ETE) 20:3 (n-3) all-cis-11,14,17-eicosatrienoicacid 306

Stearidonic acid (SDA) 18:4 (n-3) all-cis-6,9,12,15-octadecatetraenoicacid 276

Linolenic acid (ALA) 18:3 (n-3) all-cis-9,12,15 -octadecatrienoic acid278

Hexadecatrienoic acid (HTA) 16:3 (n-3) all-cis-7,10,13 -hexadecatrienoicacid 250

In a preferred embodiment of the first aspect of the invention, theomega 3 fatty acid is selected from the list consisting of:eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alphaliniolenic acid (ALA), stearidonic acid (SA), eicosatetraenoic acid(ETA), or any combination thereof. In a preferred embodiment of thefirst aspect of the invention, the omega 3 fatty acid iseicosapentaenoic acid (EPA). As is shown in example 1, a minimum of3.000 mg (3.0 g), preferably 3.400 mg (3.4 g) of EPA is required toobserve clinically useful outcomes.

In a further preferred embodiment of the first aspect of the invention,the omega 3 fatty acids are a combination of eicosapentaenoic acid (EPA)and docosahexaenoic acid (DHA), or any of their salts, ester, solvates,prodrugs, derivatives or analogs of EPA and DHA, or any combinationthereof. In a still further preferred embodiment of the first aspect ofthe invention, eicosapentaenoic acid (EPA) and docosahexaenoic acid(DHA) are use in a mass ratio from 1:1 to 5:1. Preferably is in therange of from 1:1 to 4:1, more preferably 1:1 to 3:1, still morepreferably 1.5:1 to 2.5:1, yet more preferably 2.1:1 to 2.4:1, mostpreferably in the range of from 2.1:1 to 2.2:1. Still more preferably,the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are in amass ratio of about 2:1.

As defined in the present invention, eicosapentaenoic acid (EPA or alsoicosapentaenoic acid), CAS Registry Number: 10417-94-4, IUPAC name(5Z,8Z,11Z,14Z,17Z)-5,8,11,14,17-icosapentaenoic acid is an omega-3fatty acid. In physiological literature, it is given the name 20:5(n-3).It also has the trivial name timnodonic acid. In chemical structure, EPAis a carboxylic acid with a 20-carbon chain and five cis double bonds;the first double bond is located at the third carbon from the omega end.Is a compound of formula (I):

or any of their salts, ester, solvates, prodrugs, derivatives or analogsthereof.

EPA is a polyunsaturated fatty acid (PUFA) that acts as a precursor forprostaglandin-3 (which inhibits platelet aggregation), thromboxane-3,and leukotriene-5 groups (all eicosanoids).

As defined in the present invention, docosahexaenoic acid (DHA) is anomega-3 fatty acid that is a primary structural component of the humanbrain, cerebral cortex, skin, sperm, testicles and retina. It can besynthesized from alpha-linolenic acid or obtained directly from maternalmilk or fish oil.DHA's structure is a carboxylic acid(-oic acid) with a22-carbon chain (docosa- is Greek for 22) and six (Greek “hexa”) cisdouble bonds (−˜);[2] the first double bond is located at the thirdcarbon from the omega end. Its trivial name is cervonic acid, itssystematic name is all-cis-docosa-4,7,10,13,16,19-hexa-enoic acid, andits shorthand name is 22:6(n-3) in the nomenclature of fatty acids. CASRegistry Number: 6217-54-5, IUPAC name(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid;Doconexent. Is a compound of formula (II):

or any of their salts, ester, solvates, prodrugs, derivatives or analogsthereof.

As used herein, the term “derivative” includes both pharmaceuticallyacceptable compounds, i.e., derivatives of the compound of formula (I)or (II) which can be used in the preparation of a medicament, such asderivatives pharmaceutically unacceptable, as these may be useful in thepreparation of derivatives pharmaceutically acceptable or thepreparation of food compositions.

Also within the scope of this invention are prodrugs of the compounds offormula (I) or (II). The term “prodrug” as used herein includes anycompound derived from a compound of formula (I) or (II), for example,esters, including carboxylic acid esters, amino acid esters, phosphateesters, sulphonate esters of metal salts, etc. carbamates, amides, etc..that, when administered to an individual is capable of providing,directly or indirectly, said compound of formula (I) or (II) in saidindividual. Advantageously, said derivative is a compound that increasesthe bioavailability of the compound of formula (I) or (II) whenadministered to an individual or enhancing the release of the compoundof formula (I) in a biological compartment. The nature of saidderivative is not critical provided it can be administered to anindividual and provides the compound of formula (I) or (II) in abiological compartment of an individual. The preparation of said prodrugmay be performed by conventional methods known to those skilled in theart.

In some embodiments, the EPA and/or DHA are in the form of a salt.Suitable salts include those formed with organic or inorganic bases.Pharmaceutically acceptable base salts include, but are not limited to,ammonium salts, alkali metal salts, for example those of potassium andsodium, alkaline earth metal salts, for example those of calcium andmagnesium, and salts with organic bases, for example dicyclohexylamine,N-methyl-D-glucomine, morpholine, thiomorpholine, piperidine,pyrrolidine, a mono-, di-or tri-lower alkylamine, for example ethyl-,tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-ordimethyl-propylamine, or a mono-, di-or trihydroxy lower alkylamine, forexample mono-, di-or triethanolamine.

In other embodiments, the EPA and/or DHA is/are in the form of an ester.Ester groups include those formed from the terminal carboxylic acidmoiety of the omega-3 fatty acid and an alcohol, such as a C₁-₁₂ alkylester, formed by reaction of the omega-3 fatty acid with an alcoholhaving from 1 to 12 carbons, preferably a C₁₋₅ alkyl ester formed byreaction of the omega-3 fatty acid with an alcohol having from 1 to 6carbons, for example a methyl, ethyl, n-propyl, isopropyl, butyl,pentyl, or hexyl ester, formed by reaction of the omega-3 fatty acidwith methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol orhexanol. Preferably, the ester is an ethyl ester or a methyl ester, morepreferably an ethyl ester.

In one preferred embodiment the EPA or salt or ester thereof comprisesEPA and/or EPA ethyl ester, and the DHA or salt or ester thereofcomprises DHA and/or DHA ethyl ester. More preferably, a combination ofeicosapentaenoic acid and docosahexaenoic acid is used (i.e. the freeacids of EPA and DHA are used, rather than salts or esters).

In a still further preferred embodiment of the first aspect of theinvention, said composition is a pharmaceutical composition whichoptionally comprises an acceptable pharmaceutical carrier and/oradditional active ingredients. More preferably, the pharmaceuticalcomposition comprises at least 50% weight omega 3 fatty acids.Preferably, the composition comprises at least 30 weight % omega-3 fattyacid, more preferably at least 40 weight % of omega-3 fatty acid, stillmore preferably at least 50 weight % omega-3 fatty acid. Preferably, thecomposition comprises at least 30 weight %, more preferably at least 40weight %, still more preferably at least 50 weight % of eicosapentaenoicacid. More preferably, the composition comprises at least 40 weight % ofa combination of eicosapentaenoic acid and docosahexaenoic acid in aweight ratio of from 1:1 to 4:1, optionally in liquid form, morepreferably at least 50 weight % of a combination of eicosapentaenoicacid and docosahexaenoic acid in a weight ratio of from 1:1 to 4:1,optionally in liquid form. In one particularly preferred embodiment, thecomposition comprises about 60 weight % of a combination ofeicosapentaenoic acid and docosahexaenoic acid in a weight ratio ofabout 2:1, optionally in liquid form.

In another preferred embodiment, the composition is an oral dosage form.More preferably the oral dosage form is selected from the groupcomprising tablets, capsules, caplets, slurries, sachets, suspensions,chewing gum, and powder formulation that may be dissolved in a liquid.In a still more preferably embodiment, the oral dosage form is asuspension. In another still more preferably embodiment, the oral dosageform is a powder.

In another preferred embodiment, the composition of the invention is afood composition or a health food supplement. Preferably, thecomposition comprises at least 30 weight % omega-3 fatty acid, morepreferably at least 40 weight % of omega-3 fatty acid, still morepreferably at least 50 weight % of omega-3 fatty acid. Preferably, thecomposition comprises at least 30 weight %, more preferably at least 40weight %, still more preferably at least 50 weight % of eicosapentaenoicacid. More preferably the composition comprises at least 40 weight % ofa combination of eicosapentaenoic acid and docosahexaenoic acid in aweight ratio of from 1:1 to 4:1, optionally in liquid form, morepreferably at least 50 weight % of a combination of eicosapentaenoicacid and docosahexaenoic acid in a weight ratio of from 1:1 to 4:1,optionally in liquid form. In one particularly preferred embodiment, thecomposition comprises about 60 weight % of a combination ofeicosapentaenoic acid and docosahexaenoic acid in a weight ratio ofabout 2:1, optionally in liquid form.

Preferred food compositions are selected, but not limited, from: abeverage, infused food, milk, yogurt, cheese, fermented milk, flavouredmilk drink, soybean milk, precooked cereals, bread, cake, butter,margarine, sauces, frying oils, vegetable oils, corn oil, olive oil,soybean oil, palm oil, sunflower oil, cottonseed oil, condiments, saladdressings, fruit juices, syrups, desserts, icings and fillings, softfrozen products, confections, chewing gum and intermediate food.

The omega fatty acids EPA and DHA or salts or esters thereof, may beadministered simultaneously, sequentially or separately. Then a secondaspect of the invention refers to a kit of parts, hereinafter kit ofparts of the invention, comprising eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA) in a mass ratio from 1:1 to 5:1. Preferablyis in the range of from 1:1 to 4:1, more preferably 1:1 to 3:1, stillmore preferably 1.5:1 to 2.5:1, yet more preferably 2.1:1 to 2.4:1, mostpreferably in the range of from 2.1:1 to 2.2:1. Still more preferably,the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are in amass ratio of about 2:1.

In a still further preferred embodiment of the second aspect of theinvention, said kit of parts is a pharmaceutical kit of parts whichoptionally comprises an acceptable pharmaceutical carrier and/oradditional active ingredients. More preferably, the additional activeingredient is a steroid, an anti-drug or a nutritional supplement. Otheragents may be additional nutritional products such as polyphenols andother antioxidants. In one preferred embodiment, the further activeingredient is a steroid.

In other preferred embodiment, the composition is substantially freefrom antioxidants selected from the list consisting of vitamin E(including tocopherols and tocotrienols), epigallocatechin-3-gallate(EGCG), vitamin C, lutein and zeaxanthin. In one preferred embodiment,the composition is substantially free from anti-oxidants. In onepreferred embodiment, the composition contains no anti-oxidants.

In another embodiment of the first aspect of the invention, said kit ofparts is a food kit of parts.

The kit of parts may comprise separate formulations of eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA). The separate formulations ofEPA and DHA may be administered sequentially, separately and/orsimultaneously (optionally repeatedly). Thus, the two active ingredientscan be administered either as a part of the same composition (food orpharmaceutical composition) or in separate compositions (food orpharmaceutical compositions). EPA can be administered prior to, at thesame time as, or subsequent to administration of DHA, or in somecombination thereof.

Be emphasized that the term “kit of parts”, “combined preparation” oralso called “juxtaposition” herein, means that the components of thecombined preparation need not be present as an union (the components inthe combination did not enter into direct interaction with each other),for example in a composition, to be available for use separately orsequentially. Thus, the term “juxtaposed” means that is not necessarilytrue combination, in view of the physical separation of the components.

Uses of the Compositions and Kit of Parts of the Invention

A third aspect of the inventions refers to the composition or the kit ofparts of the invention, for use in therapy or for use as a medicament ormedicine.

The term “medicine” or “medicament” as used herein refers to anysubstance used for prevention, diagnosis, alleviation, treatment or cureof disease in man and/or animals.

As shown in examples of the present invention, the use of EPA and DHA inthe indicated ratios and dosages, provides a particularly effectivetherapy for those conditions and avoids the side effects of steroids ifindicated. Currently there is no therapy to improve vision and fieldtest in patients with optic nerve damage due to glaucoma.

A fourth aspect of the invention refers to the composition or the kit ofparts of the invention, for its use in the treatment, amelioration orprevention of diseases which involve damage to the nervous system, asthe peripheral nervous system neuropathy and glaucoma.

In a preferred embodiment of the fourth aspect of the invention, thediseases which involve damage to the nervous system is selected from thegroup consisting of 2^(nd) cranial (optic) nerve neuropathy, 3^(rd)cranial nerve neuropathy (occulomotor), 4^(th) cranial nerve neuropathy(trochlear), 6^(th) cranial nerve neuropathy (abducent), 7^(th) nerveneuropathy (facial), optic nerve damage, and other eye pathologies dueto inflammation.

Optic nerve damage can occur mainly due to glaucoma, ischaemia,inflammation or trauma.

In a more preferred embodiment of the fourth aspect of the invention,the optic nerve damage is selected from the group consisting of opticnerve damage due to glaucoma, ischaemic optic neuropathy (ION), andoptic neuritis, or any combination thereof. In another preferredembodiment of the fifth aspect of the invention, the eye pathology dueto inflammation is selected from the group consisting of scleritis,thyroid eye disease, chronic uveitis, vernal and atopickeratoconjunctivitis, conjunctival and corneal wounds, A particularembodiment of the fourth aspect of the invention refers to thecomposition or the kit of parts of the invention, for its use in thetreatment, amelioration or prevention of glaucoma.

The precise dosage of the further active ingredient will vary with thedosing schedule, the oral potency of the particular agent chosen, theage, size, sex and condition of the subject, the nature and severity ofthe disorder to be treated, and other relevant medical and physicalfactors. Thus, a precise pharmaceutically effective amount cannot bespecified in advance, but can be readily determined by the caregiver orclinician. An appropriate amount can be determined by routineexperimentation from animal models and human clinical studies. Forhumans, an effective dose will be known or otherwise able to bedetermined by one of ordinary skill in the art.

The medicament of the invention may advantageously be administered in asingle daily dose, or the total daily dosage may be administered indoses of two, three or four times daily. Preferably, the EPA and DHA, ora salt or an ester thereof, is for administration once per day or twiceper day.

In a more preferred embodiment, the pharmaceutical composition or kit ofparts of the invention can be administered one or more times a day, forexample, 1, 2, 3 or 4 times a day, in a typical total daily amount to beabove 5 g per day of omega 3 fatty acids, more preferably to be above 5g per day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),and more preferably comprised between 5 g to 15 g per day. Preferably,the combined dosage is from 7.5 g to 10 g per day. In a more preferredembodiment, the pharmaceutical composition or kit of parts of theinvention can be administered in a dose wherein the combined EPA and DHAis such that the arachidonic acid/eicosapentaenoic acid mass ratio inthe blood is in the range of 0.8 to 3 preferably between 1 to 1.5 .

A fifth aspect of the invention refers to the use of the foodcomposition of the invention, for the treatment, amelioration orprevention of diseases which involve damage to the nervous system, asthe peripheral nervous system neuropathy and glaucoma.

In a preferred embodiment of the fifth aspect of the invention, thediseases which involve damage to the nervous system is selected from thegroup consisting of 2^(nd) cranial (optic) nerve neuropathy, 3^(rd)cranial nerve neuropathy (occulomotor), 4^(th) cranial nerve neuropathy(trochlear), 6^(th) cranial nerve neuropathy (abducent), 7^(th) nerveneuropathy (facial), optic nerve damage, and other eye pathologies dueto inflammation.

Optic nerve damage can occur mainly due to glaucoma, ischaemia,inflammation or trauma.

In a more preferred embodiment of the fifth aspect of the invention, theoptic nerve damage is selected from the group consisting of optic nervedamage due to glaucoma, ischaemic optic neuropathy (ION), and opticneuritis, or any combination thereof. In another preferred embodiment ofthe fifth aspect of the invention, the eye pathology due to inflammationis selected from the group consisting of scleritis, thyroid eye disease,chronic uveitis, keratoconjunctivitis, conjunctival and corneal wounds,A particular embodiment of the fifth aspect of the invention refers tothe use of the food composition of the invention for the treatment,amelioration or prevention of glaucoma. More preferably, the compositionor the kit of parts of the invention is for use in the treatment of apatient population that is poorly responsive or nonresponsive tosteroids.

In a more preferred embodiment, the food composition of the inventioncan be administered one or more times a day, for example, 1, 2, 3 or 4times a day, in a typical total daily amount to be above 5 g per day ofomega 3 fatty acids, more preferably to be above 5 g per day ofeicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and morepreferably comprised between 5 g to 15 g per day. Preferably, thecombined dosage is from 7.5 g to 10 g per day. In a more preferredembodiment, the pharmaceutical composition or kit of parts of theinvention can be administered in a dose wherein the combined EPA and DHAis such that the arachidonic acid/eicosapentaenoic acid mass ratio inthe blood is in the range of 0.8 to 3 preferably between 1 to 1.5.

The therapy of the invention has been shown to be particularly effectivefor treatment of the indicated conditions. Administrations of EPA andDHA in the doses and ratios used have been shown to result in improvedvision in patient and/or improved symptoms. In patients with optic nervedamage due to glaucoma, the inventor have seen improvement in visualacuity and in the field test. This suggests that high doses EPA and DHAin the doses and ratios used can be beneficial to provideneuroprotection for the optic nerve.

It is believed that the compositions of the invention removesneuroinflammation and provides neuroregeneration of the cranial nerveaxons. It also acts as a potent anti-inflammatory agent for the brainand orbit.

In a preferred embodiment, the condition is optic neuropathy due toglaucoma/inflammation/ischaemia/toxicity or surgery. The therapy of theinvention has been shown to improve the visual acuity and the fieldtest, probably due to neuroregeneration and removal ofneuroinflammation.

In a preferred embodiment, the condition is due to 3/4/6 cranial nerveneuropathy causing diplopia. The therapy of the invention has been shownto provide complete resolution of the neuropathy. This is probably dueto neuroregeneration and removal of neuroinflammation.

In a preferred embodiment, the condition is facial nerve neuropathy. Thetherapy of the invention has been shown to provide complete resolutionof the neuropathy.

In a preferred embodiment, the condition is any of the cranial nerveneuropathies. The present invention may provide complete resolution dueto neuroregeneration and removal of neuroinflammation.

In a preferred embodiment, the condition is scleritis. The compositionof the invention has been shown to improve the symptoms and signs of thepatients. This is probably due to resolution of neuroinflammation.

In a preferred embodiment, the condition is due to inflammation in oraround the eye e.g. thyroid eye disease, chronic uveitis, vernal oratopic keratoconjunctivitis. The composition of the invention has beenshown to improve the symptoms and signs of these patients. This isprobably due to resolution of neuroinflammation.

In a preferred embodiment, the condition is due to corneal orconjunctival wound. The composition of the invention has been shown toimprove the symptoms and signs of these patients.

Definations

As it used here, the terms “active ingredient”, “active substance”,“active pharmaceutical substance”, “active principle” or “activepharmaceutical ingredient” means any component that potentially providesa pharmacological activity or another different effect in the diagnosis,cure, mitigation, treatment or prevention of a disease, or that affectthe structure and function of the human body and of other animals. Theterm includes those components that promote a chemical change in theelaboration of the medicament and that are present in the same in apredicted modified form that provides the specific activity or theeffect.

Either compositions of the present invention, as well as the kit ofparts, can be formulated for its administration in an animal and morepreferably in a mammal, including humans, in a variety of forms known inthe state of the art. Therefore, they can be included, but not limitedto, sterile aqueous solution or in biological fluids, such as serum. Theaqueous solutions could be buffered or not and they can contain otheractive or inactive ingredients as well. The additional componentsinclude salts to modulate ionic strength, preservatives, including butnot limited to, antimicrobial agents, antioxidants, chelating agents andsimilar, and nutrients including glucose, dextrose, vitamins andminerals. Alternatively, the compositions may be prepared for itsadministration in solid form. Compositions can be combined with othervarious vehicles or inert excipients, including but not limited to:agglutinating agent such as microcrystalline cellulose, tragacanth,gelatin; excipients such as starch or lactose; dispersant agents such asalginic acid of maize starch; lubricants such as magnesium stearate;gliding agents such as colloidal silicon dioxide; sweetener such assucrose or saccharine; or aromatic agents such as mint or methylsalicylate.

The term “medicament”, as it is used in this report, makes reference toany substance used for prevention, diagnosis, relief, treatment or cureof diseases in humans and animals. In the context of the presentinvention, the disease is a diseases which involve damage to the nervoussystem.

Such compositions or combined preparations and/or its formulations maybe administered in an animal, including a mammal and therefore humans,in a variety of forms, including but not limited to, intraperitoneal,intravenous, intramuscular, subcutaneous, intrathecal, intraventricular,oral, enteral, parenteral, intranasal or topic.

The dose to obtain an amount therapeutically effective depends on avariety of factors, such as for instance, age, sex, weight, tolerance ofthe mammal. In the sense used in this description, the term “amounttherapeutically effective” refers to the amount of omega 3 fatty acids,preferably eicosapentaenoic acid (EPA), and more preferably acombination of eicosapentaenoic acid (EPA) and docosahexaenoic acid(DHA), that produce the desired effect and in general it is determinedamong other factors, by the intrinsic characteristics of the prodrug,derivatives or analogs and by the therapeutic effect to be obtained. The“adjuvant” and “vehicles pharmaceutically acceptable” that could be usedin such compositions are well known vehicles in the field.

As used in the specification and the appended claims the term“pharmaceutically acceptable carrier” is intended to include formulationused to stabilize, solubilize and otherwise be mixed with activeingredients to be administered to living animals, including humans. Thisincludes any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration. Except insofar asany conventional media or agent is incompatible with the activecompound, such use in the compositions is contemplated.

The invention now will be described with respect to the followingexamples; however, the scope of the present invention is not intended tobe limited thereby.

EXAMPLES Example 1

Method and Materials : A pilot study of 10 eyes with advanced opticnerve damage due to glaucoma. All eyes had reduced visual acuity andreduced field test. They were treated with omega 3 which consisted ofpurified ethyl esters rich in EPA (400 mg) and DHA (200 mg) per gram forthe liquid formulation. The dosage used in this pilot study was 15 ml to20 ml of liquid formulation providing approximately 5.1 g to 6.8 g ofEPA and 2.4 g to 3.2 g of DHA per day. The dosage was divided into twodaily doses of 7.5 to 10 ml each. The dose was adjusted so that theblood AA/EPA ratio was within 1 to 1.5. The intraocular pressures an alleyes were well controlled with anti-glaucomatous drops.

Study 1 Results : The visual acuity was recorded using the EDTRSelectronic chart at 6 weeks and 3 months. Visual field testing was alsorecorded with a field testing machine (Zeiss, Humphreys).

FIG. 1 shows the number of lines gained and the number of eyes over thestudy period. There is an increase of 1.5 lines of visual acuity at 6weeks and 2.1 lines at 3 months. In all cases the visual field testinghas improved. The use of prior art does not result in any therapeuticbenefits to subjects with this ophthalmological conditions. Inparticular, the levels of the omega-3 fatty acid, eicosapentaenoic acid(EPA), in each of the prior art is far too low to have any therapeuticeffect. It is this critical threshold of EPA required to induce atherapeutic effect that is the discovery of this patent application.

The FIG. 2 shows an example of a 65 years old male with controlledintraocular pressures with anti-glaucoma drops. Field testing shows theimprovement within 3 months of starting with 10 g per day of thecomposition of the invention. The visual acuity also improved by 3.5lines within the 3 months. There is no previous art to show anyimprovement in vision acuity or any improvement in optic nerve functioni.e. visual field.

The FIG. 3 shows another example of a 53 years old man with advancedglaucoma. His intraocular pressures are controlled withanti-glaucomatous eye drops. His visual acuity in the left eye was 20/50and has an advanced field loss as shown the field test. He was startedon 8 g of the composition of the invention per day. At 2.4 months hisgained 2 lines of vision and his field test improved as shown. There isno previous art to show any clinical improvement in vision or fieldtest.

Conclusion of study 1: There are no current therapies to improve visionand field test in patients with glaucomatous optic nerve damage. Fromour study, our invention can be used to improve visual acuity and visualfield in patients with optic nerve damage due to glaucoma. Since thereis no existing treatment for the optic nerve damage due to glaucoma tostop progression of the disease, the positive clinical improvementsobtained in this pilot study should be considered striking since 100% ofthe eyes had an increase in visual acuity and field testing. There is noprevious art to show any improvement in vision or field test. This againindicates the discover in this patent application that a minimum of3.000 mg, preferably 3.400 mg of EPA is required to observe clinicallyuseful outcomes.

Example 2

Method and Materials: A pilot study of 10 eyes with optic nerve damagedue to ischaemia, inflammation and post trauma. These patients had aminimum of 6 months post optic nerve damage before starting on ourtreatment. They were treated with omega 3 which consisted of purifiedethyl esters rich in EPA (400 mg) and DHA (200 mg) per gram for theliquid formulation. The dosage used in this pilot study was 15 ml to 20ml of liquid formulation providing approximately 5.1 g to 6.8 g of EPAand 2.4 g to 3.2 g of DHA per day. The dosage was divided into two dailydoses of 7.5 to 10 ml each. The dose was adjusted so that the bloodAA/EPA ratio was within 1 to 1.5.

Study 2 Results: The visual acuity was recorded using the EDTRSelectronic chart at 6 weeks 3 months and 4.5 months.

FIG. 4 shows the number of lines gained and the number of eyes over theperiod of 4.5 months. There is an increase of 1.6 lines of visual acuityat 6 weeks, 2.4 lines at 3 months and 2.5 lines at 4.5 months.

There was also improved visual field testing in all the cases that weretested.

FIG. 5 shows an example of a 55 years old man who had ischaemic opticneuropathy 6 months previous to presentation in the clinic. His visualacuity was 20/50. He was started on 10 g/day according to the invention.5 months following treatment his vision improved by 4 lines and thevisual field test improved as shown.

FIG. 6 shows an example of a 15 years old boy who presented 14 monthsfollowing a road traffic accident. His visual acuity was 20/40 and hadoptic nerve damage as shown with the field test. He was started on 7.5g/day of the composition of the invention. 5.5 months followingtreatment his visual acuity improved by 2.5 lines and the field test hasimproved as shown.

Conclusion of study 2: The invention can be used to improve visualacuity and visual fields in patients with optic nerve damage due toinflammation/ischaemia or trauma. The use of prior art does not resultin any therapeutic benefits to subjects with this ophthalmologicalconditions. In particular, the levels of the omega-3 fatty acid,eicosapentaenoic acid (EPA), in each of the prior art is far too low tohave any therapeutic effect.

Example 3

Two patients with scleritis who are only controlled with 10 mg ofprednisolone had to stop due to the side effects of the steroid. In bothcases, using the invention of 8 g per day of EPA and DHA were used tocontrol their symptoms over at least 1 year follow up.

Example 4

The invention was used in four patients with 4^(th) cranial nerveneuropathy, three patients with 3^(rd) nerve neuropathy, three patientswith 6^(th) nerve neuropathy and 2 patients with 7^(th) cranial nerveneuropathy. The symptoms of the patients resolved within 2 to 3 monthsby using 7.5 g to 10 g per day of EPA and DHA and having a ratio ofAA/EPA within 1 to 1.5.

Example 5

The invention was used in 3 patients with moderate thyroid eye disease.The patients were controlled with 10 mg of prednisolone or with 7,5 g to10 g of EPA and DHA and having a AA/EPA ratio between 1 to 1.5.

Example 6

Three patients with more than 6 months of nonhealing corneal epithelialdefects were treated with the invention. There was complete healingwithin 2 to 3 months with 7.5 g to 10 g of EPA and DHA and having aAA/EPA ratio between 1 to 1.5.

1-20. (canceled)
 21. A composition for treating diseases involvingdamage to the nervous system comprising between 3 g and 15 g ofeicosapentaenoic acid and docosahexaenoic acid, in a mass ratio EPA:DHAfrom 1:1 to 5:1, for use in the treatment, amelioration or prevention ofoptic nerve damage.
 22. The composition according to claim 21, whereinthe optic nerve damage is selected from the group including optic nervedamage due to glaucoma, ischemic optic neuropathy (ION), and opticneuritis.
 23. The composition according to claim 22, for use in thetreatment, amelioration, or prevention of optic neuritis.
 24. Thecomposition according to claim 21, for use in the treatment,amelioration, or prevention of glaucoma.
 25. The composition accordingto claim 21, wherein the amount of eicosapentaenoic acid anddocosahexaenoic acid administered comprises between 3 g to 15 g per day.26. The composition according to claim 25, wherein the amount ofeicosapentaenoic acid and docosahexaenoic acid administered is greaterthan 7.5 g per day.
 27. The composition according to claim 26, whereinthe amount of eicosapentaenoic acid and docosahexaenoic acidadministered is between 7.5 g and 10 g per day.
 28. The compositionaccording to claim 21, wherein the composition is a pharmaceuticalcomposition.
 29. The composition according to claim 21, wherein thecomposition is a food composition.
 30. The composition according toclaim 21, wherein the arachidonic acid/eicosapentaenoic acid mass ratioin the blood is in the range of 0.8 to 3, preferably from 1 to 1.5.